The presence of a fragmented QRS complex (fQRS) in two contiguous leads of a standard 12-lead electrocardiogram (ECG) has been shown to be an indicator of myocardial scar in multiple different populations of cardiac patients. QRS fragmentation is also a predictor of adverse prognosis in acute myocardial infarction, coronary artery disease, and ischemic cardiomyopathy and a prognostic tool in structural heart diseases. An increased risk of sudden cardiac death associated with fQRS has been documented in patients with ischemic cardiomyopathy and hypertrophic cardiomyopathy. However, fQRS is also frequently observed in apparently healthy subjects. Thus, a more detailed classification of different QRS fragmentations is needed to identify the pathological fragmentation patterns and refine the role of fQRS as a risk marker of adverse cardiac events and sudden cardiac death. In most studies fQRS has been defined by the presence of an additional R wave (R′), or notching in the nadir of the S wave, or the presence of >1 R′ in two contiguous leads corresponding to a major coronary territory. However, this approach does not discriminate between minor and major fragmentations and the location of the fQRS is also neglected. In addition to this, the method is susceptible to large interobserver variability. We suppose that some fQRS subtypes result from conduction delays in the His-Purkinje system, which is a benign finding and thus can weaken the prognostic values of fQRS. The classification of fQRSs to subtypes with unambiguous definitions is needed to overcome the interobserver variability related issues and to separate fQRSs caused by myocardial scarring from benign normal variants. In this paper, we review the anatomic correlates of fQRS and the current knowledge of prognostic significance of fQRS. We also propose a detailed fQRS classification for research purposes which can later be simplified after the truly pathological morphologies have been identified. The research material of our study consist of 15,245 ECGs from the random general population and approximately six thousands (n = 6,241) ECGs from subjects with a known cardiac disease.

BackgroundDiabetes predisposes to sudden cardiac death (SCD). However, it is uncertain whether greater proportion of cardiac deaths are sudden among diabetes patients than other subjects. It is also unclear whether the risk of SCD is pronounced already early in the course of the disease. The relationship of impaired glucose tolerance (IGT) and SCD is scarcely documented.MethodsA general population cohort of 10594 middle-aged subjects (mean age 44 years, 52.6 % male, follow-up duration 35–41 years) was divided into diabetes patients (n = 82), subjects with IGT (n = 3806, plasma glucose ≥9.58 mmol/l in one-hour glucose tolerance test), and controls (n = 6706).ResultsDiabetes patients had an increased risk of SCD after adjustment confounders (hazard ratio 2.62, 95 % confidence interval 1.46–4.70, p = 0.001) but risk for non-sudden cardiac death was similarly increased and the proportion of SCD of cardiac deaths was not increased. The SCD risk persisted after exclusion of subjects with baseline cardiac disease or non-fatal cardiac events during the follow-up. Subjects with IGT were at increased risk for SCD (univariate hazard ratio 1.51; 95 % confidence interval 1.31–1.74; p < 0.001) and also for non-sudden cardiac deaths and non-fatal cardiac events but adjustments for other risk factors attenuated these effects.ConclusionsDiabetes was associated with increased risk of SCD but also the risk of non-sudden cardiac death was similarly increased. The proportion of cardiac deaths being sudden in subjects with diabetes was not increased. The higher SCD risk in diabetes patients was independent of known cardiac disease at baseline or occurrence of non-fatal cardiac event during the follow-up.

Original ArticleBackground-Prevalence and prognostic significance of abnormal P terminal force (PTF) in the general population are not known. The aim of this study was to assess the prevalence of abnormal PTF and to compare clinical outcomes of middleaged subjects with and without the PTF. Methods and Results-The presence of PTF was assessed in a cohort of 10 647 middle-aged subjects (mean age [SD], 44[8] years; 47.2% female). The subjects were followed 35 to 41 years, and data on mortality and hospitalizations were obtained from national registers. Primary outcomes were all-cause mortality, cardiac mortality, and arrhythmic death. Secondary outcomes were hospitalization because of congestive heart failure, coronary heart disease, new onset atrial fibrillation, and stroke. The Cox proportional hazards model was used to assess the risk for death (all-cause), and the Fine and Gray competing risks model was used for other outcomes. The prevalence of PTF 0.04 to 0.049, 0.05 to 0.059, and ≥0.06 mm•s were 4.8%, 1.5%, and 1.2%, respectively. Subjects presenting PTF ≥0.04 mm•s were at increased risk for death, cardiac death, and congestive heart failure, and subjects presenting PTF ≥0.06 mm•s were at increased risk for atrial fibrillation. However, after adjustment for potential confounding factors, an increased risk was observed only for death (hazard ratio, 1.76; 95% confidence interval, 1.45-2.12; P<0.001) and atrial fibrillation (hazard ratio, 1.91; 95% confidence interval, 1.34-2.73; P<0.001) in subjects presenting PTF ≥0.06 mm•s. Conclusions-PTF ≥0.04 mm•s is a relatively common finding in a 12-lead ECG of middle-aged subjects. PTF ≥0.06 mm•s is associated with increased risk for atrial fibrillation and death in the general population. (Circ Arrhythm Electrophysiol.

Key Points Question Are there readily modifiable risk factors associated with the risk of atrioventricular block? Findings In this population-based cohort study of 6146 community-dwelling individuals, elevated blood pressure and blood glucose levels were associated with the development of atrioventricular block. Population-attributable risk calculations suggest that elevated blood pressure and glucose levels may be associated with more than half of all cases of atrioventricular block. Meaning Optimizing blood pressure and glucose level control may serve as effective strategies to prevent clinically relevant conduction disease and pacemaker implantation.

ObjectiveWe investigated whether combining several ECG abnormalities would identify general population subjects with a high sudden cardiac death (SCD) risk.MethodsIn a sample of 6830 participants (mean age 51.2±13.9 years; 45.5% male) in the Mini-Finland Health Survey, a general population cohort representative of the Finnish adults aged ≥30 years conducted in 1978–1980, we examined their ECGs, following subjects for 24.3±10.4 years. We analysed the association between individual ECG abnormalities and 10-year SCD risk and developed a risk score using five ECG abnormalities independently associated with SCD risk: heart rate >80 beats per minute, PR duration >220 ms, QRS duration >110 ms, left ventricular hypertrophy and T-wave inversion. We validated the score using an external general population cohort of 10 617 subjects (mean age 44.0±8.5 years; 52.7% male).ResultsNo ECG abnormalities were present in 4563 subjects (66.8%), while 96 subjects (1.4%) had ≥3 ECG abnormalities. After adjusting for clinical factors, the SCD risk increased progressively with each additional ECG abnormality. Subjects with ≥3 ECG abnormalities had an HR of 10.23 (95% CI 5.29 to 19.80) for SCD compared with those without abnormalities. The risk score similarly predicted SCD risk in the validation cohort, in which subjects with ≥3 ECG abnormalities had HR 10.82 (95% CI 3.23 to 36.25) for SCD compared with those without abnormalities.ConclusionThe ECG risk score successfully identified general population subjects with a high SCD risk. Combining ECG risk markers may improve the risk stratification for SCD.

The presented paper-to-digital conversion and digital measurement process is an accurate and reliable method, enabling efficient storing and analysis of paper ECGs.

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models. Methods: Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell–derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non–cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations. Results: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)–related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models. Conclusions: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.

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